Preferential networks of the mediodorsal nucleus and centromedian-parafascicular complex of the thalamus-A DTI tractography study

Distinct thalamic nuclei, like the mediodorsal (MD) nucleus and the centromedian/parafascicular complex (CM/Pf), are embedded in different basal ganglia—thalamocortical loops, which were shown to integrate cognitive and emotional aspects of human behavior. Despite well described connections on a microscopic scale, derived from tracing studies in animals, little is known about the intrinsic anatomical connections of these nuclei in humans. This lack of knowledge limits not only interpretation of functional imaging studies but also estimation of direct effects of deep brain stimulation which treats diseases as different as epilepsy or major depression. Therefore, non‐invasive diffusion tensor imaging (DTI) studies are key to analyzing connectivity patterns and elaborate approaches to close this gap. For our study, we explored the structural connectivity of the MD thalamic nuclei and the CM/Pf complex towards five cortical and six subcortical regions by using a preferential fiber calculation. We found both thalamic nuclei to be preferentially associated to distinct networks: whereas the MD is preferentially connected to prefrontal and limbic cortical regions, the CM is linked to subcortical regions. The anterior insula was the only cortical region associated with the subcortical network of the CM and the cortical network of the MD comprised one subcortical hub, the caudate nucleus, suggesting an integrative role of these two regions. Adding to predescribed anatomical tract tracing connectivities in animal studies, our finding lends support to the existence of similar basal ganglia‐thalamocortical circuits in humans and we could show a robust distinction of preferential connectivity for both thalamic nuclei. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

The anatomo-functional connectivity of language revisited. New insights provided by electrostimulation and tractography

In addition to the seminal lesion studies of aphasiology, the development of functional neuroimaging has allowed a better understanding of the neural foundations of language. However, despite a substantial improvement in the knowledge of the cortical networks organization, the underlying subcortical association circuits have received less attention. Recent advances in fiber tracking using diffusion tensor imaging, combined with personal studies using intraoperative electrostimulation, which temporarily inactivates restricted regions during brain surgery, have enabled to map language pathways in humans with spatiotemporal resolution unmatched by other techniques. On the basis of these new insights, my purpose is to revisit the anatomo-functional connectivity of language. First, I discuss the role of the white bundles thought to be essential for language, with special emphasis regarding the structure-function relationships pertaining to the distinct subcomponents of language. Second, I propose an integrative view of connectivity, that considers language as the final product of the well-synchronized functioning of parallel distributed cortico-subcortical networks.     

Corticostriatal connectivity fingerprints: Probability maps based on resting‐state functional connectivity

Over the last decade, structure–function relationships have begun to encompass networks of brain areas rather than individual structures. For example, corticostriatal circuits have been associated with sensorimotor, limbic, and cognitive information processing, and damage to these circuits has been shown to produce unique behavioral outcomes in Autism, Parkinson's Disease, Schizophrenia and healthy ageing. However, it remains an open question how abnormal or absent connectivity can be detected at the individual level. Here, we provide a method for clustering gross morphological structures into subregions with unique functional connectivity fingerprints, and generate network probability maps usable as a baseline to compare individual cases against. We used connectivity metrics derived from resting‐state fMRI (N = 100), in conjunction with hierarchical clustering methods, to parcellate the striatum into functionally distinct clusters. We identified three highly reproducible striatal subregions, across both hemispheres and in an independent replication dataset (N = 100) (dice‐similarity values 0.40–1.00). Each striatal seed region resulted in a highly reproducible distinct connectivity fingerprint: the putamen showed predominant connectivity with cortical and cerebellar sensorimotor and language processing areas; the ventromedial striatum cluster had a distinct limbic connectivity pattern; the caudate showed predominant connectivity with the thalamus, frontal and occipital areas, and the cerebellum. Our corticostriatal probability maps agree with existing connectivity data in humans and non‐human primates, and showed a high degree of replication. We believe that these maps offer an efficient tool to further advance hypothesis driven research and provide important guidance when investigating deviant connectivity in neurological patient populations suffering from e.g., stroke or cerebral palsy. Hum Brain Mapp 38:1478–1491, 2017. © 2016 Wiley Periodicals, Inc.     

Neural circuits revealed by axon tracing and mapping cadherin expression in the embryonic chicken cerebellum

Fiber connections of the cerebellar cortex are organized into distinct parasagittal domains. Each domain expresses a unique subset of various genes. Brain structures that are directly connected to the cerebellar cortex, such as the deep cerebellar nuclei and the inferior olivary nucleus, show a similarly differential pattern of connectivity and gene expression. For example, several members of the cadherin family of adhesion molecules are expressed differentially in the subdivisions of the cerebellar system in chicken and mouse. Little is known, however, about how the molecular maps in the different parts of the cerebellum relate to each other in terms of connectivity. Here, we mapped the expression of three cadherins (cadherin-8, protocadherin-7, and protocadherin-10) in the cerebellar system of the chicken embryo. By simultaneously tracing axonal connections with biotinylated dextran amine, we demonstrate that cortical domains and deep nuclear portions as well as their fiber connections have a matching expression profile for protocadherin-10 in the posterior part of the cerebellum. Based on the tracing results for protocadherin-10 and the comparative expression mapping of all three cadherins, the cortical projection domains of the three deep cerebellar nuclei were determined in the posterior part of the cerebellum. Results were extrapolated to the rest of the cerebellar cortex. Our results provide direct experimental support for the notion that cadherins are markers for neural circuits in the brain. Moreover, we show that the expression pattern of all three cadherins confers unique identities to the Purkinje cell domains.     

Hierarchical connectivity and connection-specific dynamics in the corticospinal-corticostriatal microcircuit in mouse motor cortex

The generation of purposive movement by mammals involves coordinated activity in the corticospinal and corticostriatal systems, which are involved in different aspects of motor control. In the motor cortex, corticospinal and corticostriatal neurons are closely intermingled, raising the question of whether and how information flows intracortically within and across these two channels. To explore this, we developed an optogenetic technique based on retrograde transfection of neurons with deletion-mutant rabies virus encoding channelrhodopsin-2, and used this in conjunction with retrograde anatomical labeling to stimulate and record from identified projection neurons in mouse motor cortex. We also used paired recordings to measure unitary connections. Both corticospinal and callosally projecting corticostriatal neurons in layer 5B formed within-class (recurrent) connections, with higher connection probability among corticostriatal than among corticospinal neurons. In contrast, across-class connectivity was extraordinarily asymmetric, essentially unidirectional from corticostriatal to corticospinal. Corticostriatal neurons in layer 5A and corticocortical neurons (callosal projection neurons similar to corticostriatal neurons) similarly received a paucity of corticospinal input. Connections involving presynaptic corticostriatal neurons had greater synaptic depression, and those involving postsynaptic corticospinal neurons had faster decaying EPSPs. Consequently, the three connections displayed a diversity of dynamic properties reflecting the different combinations of presynaptic and postsynaptic projection neurons. Collectively, these findings delineate a four-way specialized excitatory microcircuit formed by corticospinal and corticostriatal neurons. The "rectifying" corticostriatal-to-corticospinal connectivity implies a hierarchical organization and functional compartmentalization of corticospinal activity via unidirectional signaling from higher-order (corticostriatal) to lower-order (corticospinal) output neurons.     

MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat

BackgroundSocial deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders.ObjectiveWe first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model.MethodsBrain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model.ResultsThe DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits.ConclusionsApplying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.     

The cortical connectivity of the prefrontal cortex in the monkey brain

One dimension of understanding the functions of the prefrontal cortex is knowledge of cortical connectivity. We have surveyed three aspects of prefrontal cortical connections: local projections (within the frontal lobe), the termination patterns of long association (post-Rolandic) projections, and the trajectories of major fiber pathways. The local connections appear to be organized in relation to dorsal (hippocampal origin) and ventral (paleocortical origin) architectonic trends. According to the proposal of a dual origin of the cerebral cortex, cortical areas can be traced as originating from archicortex (hippocampus) on the one hand, and paleocortex, on the other hand, in a stepwise manner (e.g., Sanides, 1969; Pandya and Yeterian, 1985). Prefrontal areas within each trend are connected with less architectonically differentiated areas, and also with more differentiated areas. Such organization may allow for the systematic exchange of information within each architectonic trend. The long connections of the prefrontal cortex with post-Rolandic regions seem to be organized preferentially in relation to dorsal and ventral prefrontal architectonic trends. Prefrontal areas are connected with post-Rolandic auditory, visual and somatosensory association areas, and with multimodal and paralimbic regions. This long connectivity likely works in conjunction with local connections to serve prefrontal cortical functions. The afferent and efferent connections of the prefrontal cortex with post-Rolandic regions are conveyed by specific long association pathways. These pathways as well appear to be organized in relation to dorsal and ventral prefrontal architectonic trends. Finally, although prefrontal areas have preferential connections in relation to dual architectonic trends, it is clear that there are interconnections between and among areas in each trend, which may provide a substrate for the overall integrative function of the prefrontal cortex. Prefrontal corticocortical connectivity may help to elucidate both region-specific and integrative perspectives on the functions of the prefrontal cortex.     

Changes in corticostriatal connectivity during reinforcement learning in humans

Many computational models assume that reinforcement learning relies on changes in synaptic efficacy between cortical regions representing stimuli and striatal regions involved in response selection, but this assumption has thus far lacked empirical support in humans. We recorded hemodynamic signals with fMRI while participants navigated a virtual maze to find hidden rewards. We fitted a reinforcement‐learning algorithm to participants' choice behavior and evaluated the neural activity and the changes in functional connectivity related to trial‐by‐trial learning variables. Activity in the posterior putamen during choice periods increased progressively during learning. Furthermore, the functional connections between the sensorimotor cortex and the posterior putamen strengthened progressively as participants learned the task. These changes in corticostriatal connectivity differentiated participants who learned the task from those who did not. These findings provide a direct link between changes in corticostriatal connectivity and learning, thereby supporting a central assumption common to several computational models of reinforcement learning. Hum Brain Mapp 36:793–803, 2015. © 2014 Wiley Periodicals, Inc .     

Examination of spinal cord tissue architecture with magnetic resonance diffusion tensor imaging

Magnetic resonance diffusion tensor imaging yields images with detailed information about tissue water diffusion. Diffusion-weighted imaging of the human spinal cord requires dedicated magnetic resonance pulse sequences that minimize the effects of subject motion, distortions, and artifacts from lipids and CSF flow. These problems are accentuated by the anatomic properties of the spinal cord (i.e., a small crosssectional dimension and a location deep inside the body). The diffusion tensor (a simplified model for complex diffusion in structured tissues) can be estimated for each image pixel by measuring diffusion along a minimum of six independent directions. It can then be used to derive mean diffusivity, diffusion anisotropy, and the dominant orientation of the diffusion process. The observation that diffusion along nerve fibers is much higher than across fibers, allows a noninvasive reconstruction of the spinal cord nerve fiber architecture. This includes not only the primary cranio-caudad running connections, but also secondary, transverse running collateral fibers. With fiber tracking, the pixel-based diffusion information can be integrated to obtain a three-dimensional view of axonal fiber connectivity between the spinal cord and different brain regions. The development and myelination during infancy and early childhood is reflected in a gradual decrease of mean diffusivity and increase in anisotropy. There are several diseases that lead to either local or general changes in spinal cord water diffusion. For therapy research, such changes can be studied noninvasively and repeatedly in animal models.     

Impaired functional but preserved structural connectivity in limbic white matter tracts in youth with conduct disorder or oppositional defiant disorder plus psychopathic traits

Youths with conduct disorder or oppositional defiant disorder and psychopathic traits (CD/ODD+PT) are at high risk of adult antisocial behavior and psychopathy. Neuroimaging studies demonstrate functional abnormalities in orbitofrontal cortex and the amygdala in both youths and adults with psychopathic traits. Diffusion tensor imaging in psychopathic adults demonstrates disrupted structural connectivity between these regions (uncinate fasiculus). The current study examined whether functional neural abnormalities present in youths with CD/ODD+PT are associated with similar white matter abnormalities. Youths with CD/ODD+PT and comparison participants completed 3.0 T diffusion tensor scans and functional magnetic resonance imaging scans. Diffusion tensor imaging did not reveal disruption in structural connections within the uncinate fasiculus or other white matter tracts in youths with CD/ODD+PT, despite the demonstration of disrupted amygdala-prefrontal functional connectivity in these youths. These results suggest that disrupted amygdala-frontal white matter connectivity as measured by fractional anisotropy is less sensitive than imaging measurements of functional perturbations in youths with psychopathic traits. If white matter tracts are intact in youths with this disorder, childhood may provide a critical window for intervention and treatment, before significant structural brain abnormalities solidify.     

Microstructural development: Organizational differences of the fiber architecture between children and adults in dorsal and ventral visual streams

Visual perceptual skills are basically mature by the age of 7 years. White matter, however, continues to develop until late adolescence. Here, we examined children (aged 5–7 years) and adults (aged 20–30 years) using diffusion tensor imaging (DTI) fiber tracking to investigate the microstructural maturation of the visual system. We characterized the brain volumes, DTI indices, and architecture of visual fiber tracts passing through white matter structures adjacent to occipital and parietal cortex (dorsal stream), and to occipital and temporal cortex (ventral stream). Dorsal, but not ventral visual stream pathways were found to increase in volume during maturation. DTI indices revealed expected maturational differences, manifested as decreased mean and radial diffusivities and increased fractional anisotropy in both streams. Additionally, fractional anisotropy was increased and radial diffusivity was decreased in the adult dorsal stream, which can be explained by specific dorsal stream myelination or increasing fiber compaction. Adult dorsal stream architecture showed additional intra‐ and interhemispheric connections: Dorsal fibers penetrated into contralateral hemispheres via commissural structures and projection fibers extended to the superior temporal gyrus and ventral association pathways. Moreover, intra‐hemispheric connectivity was particularly strong in adult dorsal stream of the right hemisphere. Ventral stream architecture also differed between adults and children. Adults revealed additional connections to posterior lateral areas (occipital‐temporal gyrus), whereas children showed connections to posterior medial areas (posterior parahippocampal and lingual gyrus). Hence, in addition to dorsal stream myelination or fiber compaction, progressing maturation of intra‐ and interhemispheric connectivity may contribute to the development of the visual system. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Dissociable corticostriatal circuits underlie goal‐directed vs. cue‐elicited habitual food seeking after satiation: evidence from a multimodal MRI study

The present multimodal MRI study advances our understanding of the corticostriatal circuits underlying goal‐directed vs. cue‐driven, habitual food seeking. To this end, we employed a computerized Pavlovian‐instrumental transfer paradigm. During the test phase, participants were free to perform learned instrumental responses (left and right key presses) for popcorn and Smarties outcomes. Importantly, prior to this test half of the participants had been sated on popcorn and the other half on Smarties – resulting in a reduced desirability of those outcomes. Furthermore, during a proportion of the test trials, food‐associated Pavlovian cues were presented in the background. In line with previous studies, we found that participants were able to perform in a goal‐directed manner in the absence of Pavlovian cues, meaning that specific satiation selectively reduced responding for that food. However, presentation of Pavlovian cues biased choice toward the associated food reward regardless of satiation. Functional MRI analyses revealed that, in the absence of Pavlovian cues, posterior ventromedial prefrontal cortex tracked outcome value. In contrast, during cued trials, the BOLD signal in the posterior putamen differentiated between responses compatible and incompatible with the cue‐associated outcome. Furthermore, we identified a region in ventral amygdala showing relatively strong functional connectivity with posterior putamen during the cued trials. Structural MRI analyses provided converging evidence for the involvement of corticostriatal circuits: diffusion tensor imaging data revealed that connectivity of caudate‐seeded white‐matter tracts to the ventromedial prefrontal cortex predicted responding for still‐valuable outcomes; and gray matter integrity in the premotor cortex predicted individual Pavlovian cueing effects.     

Putamen coactivation during motor task execution

Models of corticostriatal motor circuitry have focused on the role of the circuit in the hemisphere of the motor cortex providing primary control (contralateral to the movement). We used functional magnetic resonance imaging and functional connectivity analyses to study circuit function in both the controlling and noncontrolling hemispheres. During the completion of a unilateral motor task with either hand, each putamen nucleus demonstrated strong coactivation with structures in both hemispheres. The putamen in the noncontrolling hemisphere (ipsilateral to the movement) coactivated more strongly with the controlling motor cortex than with the noncontrolling cortex. These findings suggest that the two corticostriatal circuits are functionally integrated. New circuit models based on functional connectivity may need to be developed.     

Social network diversity and white matter microstructural integrity in humans

Diverse aspects of physical, affective and cognitive health relate to social integration, reflecting engagement in social activities and identification with diverse roles within a social network. However, the mechanisms by which social integration interacts with the brain are unclear. In healthy adults (N = 155), we tested the links between social integration and measures of white matter microstructure using diffusion tensor imaging. Across the brain, there was a predominantly positive association between a measure of white matter integrity, fractional anisotropy (FA), and social network diversity. This association was particularly strong in a region near the anterior corpus callosum and driven by a negative association with the radial component of the diffusion signal. This callosal region contained projections between bilateral prefrontal cortices, as well as cingulum and corticostriatal pathways. FA within this region was weakly associated with circulating levels of the inflammatory cytokine interleukin-6 (IL-6), but IL-6 did not mediate the social network and FA relationship. Finally, variation in FA indirectly mediated the relationship between social network diversity and intrinsic functional connectivity of medial corticostriatal pathways. These findings suggest that social integration relates to myelin integrity in humans, which may help explain the diverse aspects of health affected by social networks.     

Topography of cortico-striatal connections in man: anatomical evidence for parallel organization

Tracing studies in non-human primates support the existence of several parallel neuronal circuits involving cerebral cortex, basal ganglia and thalamus. Distinct functional loops were proposed to underlie multiple aspects of normal and pathological behaviour in man. We present here the first anatomical evidence for separate corticostriatal systems in humans. Neural connections of the sensorimotor and prefrontal cortex to the striatum were studied in one human brain using the Nauta method for anterogradely degenerating axons. Axons originating from a lesion in the left sensorimotor cortex, including the face area, were found to terminate in the superolateral part of the ipsilateral putamen, forming a narrow band in its posterior part. Inside the band, the distribution of degenerating axons was inhomogeneous; high-density clusters of approximately 2.5 mm in diameter were separated by regions with less dense cortical projections. Axons originating from a small lesion in the fundus of the right superior frontal sulcus were found in the upper part of the ipsilateral caudate nucleus. The existence of discrete and anatomically segregated terminal patches originating from distinct cortical regions suggests parallel organization of cortico-striatal connections in man.     

Disentangling disorders of consciousness: Insights from diffusion tensor imaging and machine learning

Previous studies have suggested that disorders of consciousness (DOC) after severe brain injury may result from disconnections of the thalamo‐cortical system. However, thalamo‐cortical connectivity differences between vegetative state (VS), minimally conscious state minus (MCS?, i.e., low‐level behavior such as visual pursuit), and minimally conscious state plus (MCS+, i.e., high‐level behavior such as language processing) remain unclear. Probabilistic tractography in a sample of 25 DOC patients was employed to assess whether structural connectivity in various thalamo‐cortical circuits could differentiate between VS, MCS?, and MCS+ patients. First, the thalamus was individually segmented into seven clusters based on patterns of cortical connectivity and tested for univariate differences across groups. Second, reconstructed whole‐brain thalamic tracks were used as features in a multivariate searchlight analysis to identify regions along the tracks that were most informative in distinguishing among groups. At the univariate level, it was found that VS patients displayed reduced connectivity in most thalamo‐cortical circuits of interest, including frontal, temporal, and sensorimotor connections, as compared with MCS+, but showed more pulvinar‐occipital connections when compared with MCS?. Moreover, MCS? exhibited significantly less thalamo‐premotor and thalamo‐temporal connectivity than MCS+. At the multivariate level, it was found that thalamic tracks reaching frontal, parietal, and sensorimotor regions, could discriminate, up to 100% accuracy, across each pairwise group comparison. Together, these findings highlight the role of thalamo‐cortical connections in patients' behavioral profile and level of consciousness. Diffusion tensor imaging combined with machine learning algorithms could thus potentially facilitate diagnostic distinctions in DOC and shed light on the neural correlates of consciousness. Hum Brain Mapp 38:431–443, 2017 . © 2016 Wiley Periodicals, Inc.     

Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer's disease and mild cognitive impairment

BackgroundBrain imaging studies of early Alzheimer's disease (AD) have shown decreased metabolism predominantly in the posterior cingulate cortex (PCC), medial temporal lobe, and inferior parietal lobe. This study investigated functional connectivity between these regions, as well as connectivity between these regions and the whole brain.MethodsFunctional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) studies were performed in subjects with early AD, mild cognitive impairment (MCI), and normal controls.ResultsThe data indicate both decreased fiber connections and disrupted connectivity between the hippocampus and PCC in early AD. The MCI group showed reduced fiber numbers derived from PCC and hippocampus to the whole brain.ConclusionsThe fMRI and DTI results confirmed decreased connectivity from both the PCC and hippocampus to the whole brain in MCI and AD and reduction in connectivity between these two regions, which plausibly represents an early imaging biomarker for AD.